This invention relates to methods for the treatment of neurodegenerative disease.
Neurodegenerative diseases include Alzheimer's disease (AD) Creutzfeldt-Jakob disease, Huntington's disease, Lewy body disease, Pick's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), neurofibromatosis, and diseases without a necessary genetic component such as brain injury, stroke, and multiple infarct dementia. Most of these diseases are typified by onset during the middle adult years and lead to rapid degeneration of specific subsets of neurons within the neural system, ultimately resulting in premature death. There are no known cures and few therapies that slow the progression of these diseases.
Alzheimer's disease (AD) is one of the most clinically important of the neurodegenerative diseases due to the high frequency of occurrence within the population and the fatal course of the disease. Two forms of the disease exist: presenile dementia, in which the symptoms emerge during middle age, and senile dementia which occurs in the elderly. Both forms of the disease appear to have the same pathology. A clear genetic predisposition has been found for presenile dementia. Familial autosomal dominant cases have been reported and the majority of individuals with trisomy 21 (Down's syndrome) develop presenile dementia after the age of 40. The genetic loci associated with familial Alzheimer's disease map to chromosomes 14, 19, and 21, with more than one locus on 21.
Pick's disease (lobar sclerosis) is expressed clinically as dementia that is essentially indistinguishable from that of Alzheimer's disease. The disease becomes symptomatic in middle adulthood and progresses relentlessly over a period of 3 to 5 years. Some of Pick's disease cases cluster in families, but the case distributions do not conform to a strictly hereditary pattern. Women are affected by the disease more often than men.
The brain in Pick's disease is atrophic. Unlike Alzheimer's disease, the atrophy is typically localized in a frontal or a temporal lobe, and it may attain extreme proportions. Histologically, the involved cortex is markedly depleted of neurons, and their absence is accentuated by a marked astrogliosis. Many residual neurons have a "ballooned" cytoplasm, and in some, there is one or more faintly eosinophilic inclusions, termed Pick bodies, whose presence is confirmed by their intense argentophilia. These bodies are formed of densely aggregated neurofilaments.
Creutzfeldt-Jakob disease was named after the two doctors from Austria who in 1920 separately described a total of six patients with peculiar neurological illnesses. Although the illnesses were not very similar, the post mortem brain tissue appeared similar when viewed under the microscope. Many of the normal brain nerve cells were dead and the tissue had numerous tiny holes, resembling a sponge, hence, the expression "spongiform encephalopathy" is also used to describe the disease.
Creutzfeldt-Jakob disease (CJD) occurs worldwide. There is approximately one new case per two million people per year with the age of onset occurring between the ages of 55 and 80. CJD can affect more than one member of a family but this is rare.
Huntington's disease is a progressive disease which is always transmitted as an autosomal dominant trait mapping to a single locus on chromosome 4. Individuals are generally asymptomatic until the middle adult years, although some patients show symptoms as early as age 15. Once symptoms appear, the disease is characterized by choreoathetotic movements and progressive dementia until death 15-20 years after the age of onset.
Autopsies of Huntington's disease patients reveal progressive atrophy of the caudate nucleus and basal ganglia. Atrophy of the caudate nucleus and the putamen is seen microscopically where there is an excessive loss of neural tissue.
Although some of the characteristic mental depression and motor symptoms associated with Huntington's may be suppressed using tricyclic antidepressants and dopamine receptor antagonists, respectively, no therapy exists for slowing or preventing the underlying disease process
Parkinson's disease is a common neurodegenerative disorder which first appears in mid to late life. Familial and sporadic cases occur, although familial cases account for only 1-2 percent of the observed cases. The neurological changes which cause this disease are somewhat variable and not fully understood. Patients frequently have nerve cell loss with reactive gliosis and Lewy bodies in the substantia nigra and locus coeruleus of the brain stem. Similar changes are observed in the nucleus basalis of Meynert. As a class, the nigrostriatal dopaminergic neurons seem to be most affected.
The disorder generally develops asymmetrically with tremors in one hand or leg and progresses into symmetrical loss of voluntary movement. Eventually, the patient becomes incapacitated by rigidity and tremors. In the advanced stages the disease is frequently accompanied by dementia.
Diagnosis of both familial and sporadic cases of Parkinson's disease can only be made after the onset of the disease symptoms. Anticholinergic compounds, such as propranolol, primidone, and levodopa, are frequently administered to modify neural transmissions and thereby suppress the symptoms of the disease, though there is no known therapy which halts or slows the underlying progression.
Lewy body disease is a preferred term which describes several common disorders causing dementia. In many hospitals this is the second most common * cause of dementia following Alzheimer's disease. The name for the disease comes from the presence of abnormal lumps called Lewy bodies which develop inside nerve cells.
The primary clinical symptom of this condition is the development of dementia, although patients may also show Parkinsonian symptoms and experience hallucinations.
Autopsy of Lewy body disease patients reveals degeneration of the substantia nigra, as would be seen in Parkinson's disease. In Lewy body dementia and Parkinson's disease, the melanin containing nerve cells of the substantia nigra die and the tissue thus appears abnormally pale in comparison to normal tissue. The cause of Lewy body disease is uncertain. However, an association with a higher apoE4 allele frequency has been noted.
Neurofibromatosis actually refers to at least two related but quite distinct diseases.
Neurofibromatosis 1 (NF1, peripheral neurofibromatosis, von Recklinghausen disease) is characterized by multiple neurofibromas, cafe au lait macules, and Lisch nodules of the iris. Some patients with NFl also show learning disabilities, macrocephaly, bony abnormalities, and a higher frequency of neural malignancies.
Neurofibromatosis 2 (NF2, central neurofibromatosis) is characterized by the appearance of bilateral vestibular schwannomas. The majority of NF2 patients develop schwannomas of cranial or peripheral nerves while a minority develop other tumors, such as meningiomas and ependymomas.
Both NF1 and NF2 are autosomal dominant disorders with nearly full penetrance and occur spontaneously 50% of the time. NF1, with an incidence of 1 in 40,000 individuals is a much more rare disorder then NF2, which has an incidence of 1 in 3,000.
Reflective of their very different clinical appearances, NF1 and NF2 are caused by two entirely different genes. The NF1 gene on chromosome 17 encodes a protein named neurofibromin. The function of neurofibromin is unclear, although it does contain a single domain with GTPase activating activity. The NF2 gene on chromosome 22 encodes the Merlin protein. The exact function of Merlin is also unknown, but it is highly homologous to a family of cytoskeleton associated proteins including moesin, ezrin, radixin, and talin.
Amyotrophic lateral sclerosis (ALS) is the most commonly diagnosed progressive motor neuron disease. The disease is characterized by degeneration of motor neurons in the cortex, brainstem, and spinal cord. Generally, the onset is between the third and sixth decade. ALS is uniformly fatal, typically within five years. The cause of the disease is unknown although some cases of familial ALS map to the sod-1 gene.
Post mortem brains from ALS patients show affected neurons of the cerebral cortex, the anterior horns of the spinal cord, and the homologues in some of the motor nuclei of the brain stem. The class of neurons affected is highly specific: first motor neurons for ocular motility, then later in the disease, sphincteric motor neurons of the spinal cord.
Although death occasionally results shortly after the onset of this symptomatic disease, the disease generally ends with respiratory failure secondary to profound generalized and diaphragmatic weakness.
Multiple Sclerosis (MS) is a neurodegenerative disease of the brain and spinal cord in which a breakdown occurs in the myelin sheathing of the nerve fibers. MS is currently incurable and treatments are few and usually result in only temporary improvements of the disease symptoms.
Brain injury, stroke, and multiple infarct dementia are injuries to the brain that have no necessary genetic component but often result in similar neuronal deficits similar to those seen in the genetic disorders described above.
Apolipoprotein E (ApoE) has been extensively studied in non-nervous tissues as one of several proteins that regulate lipid metabolism and transport. ApoE facilitates cholesterol transport between different cell types and different organs. Specifically, it binds to large lipid-protein particles (called lipoproteins) and increases their ability to transport cholesteryl esters.
The mature form of ApoE, found in human plasma and cerebrospinal fluid (CSF), is a single, glycosylated, 37 kDa polypeptide containing 299 amino acids. There is some evidence that ApoE may coordinate the mobilization and redistribution of cholesterol in repair, growth, and maintenance of myelin and neuronal membranes during development or after sciatic nerve injury. In the brain, ApoE appears to coordinate the redistribution of cholesterol and phospholipids. Removal of the apoE gene by gene disruption or "knockout," appears to cause some age-dependent reduction of synaptic contacts in the cortex and impairment of reinnervation in the hippocampus.
In humans there are three major isoforms of ApoE (E4, E3 and E2) differing by a single unit of net charge which can be easily detected by isoelectrofocusing. These isofonns are expressed from multiple alleles at a single apoE genetic locus, giving rise to three common homozygous phenotypes (E4/4, E3/3 and E2/2) and three common heterozygous phenotypes (E4/3, E4/2, and E3/2).
The allele frequency of apoE4 is markedly increased in sporadic and late onset familial Alzheimer's disease (AD). As many as 80% of clinical cases of AD (aged between 65 and 75 years) carry the E4 allele compared to only 15% in the normal population.
Drugs for the treatment of patients with neurodegenerative disease, such as Alzheimer's disease, are few in number despite the need for such therapies. Only two FDA approved drugs are currently approved for treating symptoms of Alzheimer's disease: tacrine (Cognex.TM. manufactured by Parke-Davis) and donepezil (Ariceptf marketed by Pfizer).